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Cornelia de Lange Syndrome (CdLS) is a rare congenital disorder characterised by distinctive facial features, growth retardation, limb abnormalities and developmental delays. It is characterised by genetic heterogeneity and also presents a broad clinical variability, with a spectrum of manifestations ranging from mild to severe, with milder phenotypes that can be difficult to ascertain based on physical characteristics. Pathogenic variations in the NIPBL gene account for the majority of cases, but variations in several other genes, including BRD4, have been identified as causative factors for non-classic or milder forms of the syndrome. This review aims to analyse the roles that BRD4 plays in the various pathways in which it is involved and to summarise current knowledge on atypical CdLS associated with BRD4 gene alterations, highlighting clinical features, molecular mechanisms, and implications for diagnostic assessment and patient care.

Maturity-Onset Diabetes of the Young Type 5 (MODY5) is caused by heterozygous pathogenic variants in the HNF1B gene, encoding the transcription factor hepatocyte nuclear factor-1β. HNF1B haploinsufficiency typically leads to young-onset non-immune diabetes and highly variable renal involvement, whose more frequent features are bilateral kidney cysts and renal hypodysplasia. Kidney cysts or echogenic kidneys can be identified by ultrasonography in the prenatal period, but the renal involvement can also start in childhood or later. Notably, a recurrent microdeletion syndrome at 17q12 (deleting HNF1B plus ~15 neighboring genes) accounts for ~40–50% of cases. The 17q12 deletion is a contiguous gene syndrome and affected individuals present with a complex phenotype, including neurodevelopmental disorders, liver and pancreas abnormalities, and other congenital defects. When counseling the patient and the parents, the clinician must consider multiple factors, including the molecular defect and the age of onset of the symptoms, with particular attention to prenatal diagnosis. A multidisciplinary approach and an early diagnosis are essential for the management of these conditions.

Bone metabolism has been rarely investigated in children affected by Neurofibromatosis type 1 (NF1). Aim of the present study was to assess bone mineral metabolism in children and adults NF1 patients, to determine the relevant factors potentially involved in the development of reduced bone mineral density (BMD), and provide possible therapeutic intervention in NF1 patients. 114 NF1 patients and sex and age matched controls were enrolled into the study. Clinical and biochemical factors reflecting bone metabolism were evaluated. Factors potentially affecting BMD were also investigated including: physical activity, sun exposure, vitamin D intake. Whenever the presence of vitamin D deficiency was recorded, cholecalciferol supplementation was started and z-score data obtained at Dual-Energy X-ray Absorptiometry (DXA) during supplementation were compared with previous ones. NF1 patients showed lower Z-scores at Dual-Energy X-ray Absorptiometry DXA than controls. Physical activity was significantly reduced in NF1 patients than in controls. Sun exposure was significantly lower in NF1 compared to control subjects. At linear regression analysis vitamin D was the most predictive factor of reduced z-score at DXA (p = 0.0001). Cholecalciferol supplementation significantly increased BMD z-score (p < 0.001). We speculated that a combination of different factors, including reduced sun exposure, possibly associated with reduced serum vitamin D levels, and poor physical activity, concur to the impaired bone status in NF1 patients. We also demonstrated that treatment with vitamin D can be effective in improving z-score value in NF1 patients, including children. In conclusion, the findings of the current study are expected to have important implications for the follow-up and prevention of osteopenia/osteoporosis in this common genetic disease.

Kabuki syndrome (KS) is a well-recognized disorder characterized by postnatal growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability. The syndrome is caused by KMT2D gene mutations or less frequently KDM6A gene mutations or deletions. We report a systematic evaluation of KS patients from Campania region of Italy; data were also compared with literature ones. We collected data of 15 subjects (8 males and 7 females with age range 10–26 years; mean age 16.9 years) with confirmed diagnosis of KS, representing the entire cohort of patients from Campania Region. Each patient performed biochemical testing and instrumental investigation. Neuro-intellectual development, cranio-facial dysmorphisms, and multisystem involvement data were collected retrospectively. For each category, type of defects and frequency of the anomalies were analyzed. Our observation shows that KS patients from Campania region have some particular and previously underscored, neurological and immunological findings. We found high prevalence of EEG’s abnormalities (43%) and MRI brain abnormalities (60%). Microcephaly resulted more common in our series (33%), if compared with major cohorts described in literature. Biochemical features of immunodeficiency and autoimmune diseases including thyroid autoimmunity, polyserositis, and vitiligo were observed with high prevalence (54.5%). Low immunoglobulins levels were a frequent finding. Lymphocyte class investigation showed significantly reduced CD8 levels in one patient. Conclusions : These data confirm great heterogeneity of clinical manifestations in KS and suggest to introduce further clinical diagnostic criteria in order to perform a correct and precocious diagnosis. What is Known • Kabuki syndrome is characterized by growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability • Immune dysfunction is a common finding but autoimmune diseases are rarely seen • Neurological features are common What is New • Some particular facial features could help gestalt diagnosis (hypertelorism, broad nasal bridge, micrognathia, tooth agenesis, cutaneous haemangiomas and strabismus) • Higher prevalence of autoimmune disorders than previously reported • Particular neurological features are present in this cohort (EEG and MRI brain abnormalities)

Smith-Magenis syndrome (SMS; OMIM #182290) is a complex genetic disorder characterized by distinctive physical features, developmental delay, cognitive impairment, and a typical behavioral phenotype. SMS is caused by interstitial 17p11.2 deletions, encompassing multiple genes and including the retinoic acid-induced 1 gene ( ), or by mutations in itself. About 10% of all the SMS patients, in fact, carry an mutation responsible for the phenotype. (OMIM *607642) is a dosage-sensitive gene expressed in many tissues and highly conserved among species. Over the years, several studies have demonstrated that (or its homologs in animal models) acts as a transcriptional factor implicated in embryonic neurodevelopment, neuronal differentiation, cell growth and cell cycle regulation, bone and skeletal development, lipid and glucose metabolisms, behavioral functions, and circadian activity. Patients with pathogenic variants show some phenotypic differences when compared to those carrying the typical deletion. They usually have lower incidence of hypotonia and less cognitive impairment than those with 17p11.2 deletions but more frequently show the behavioral characteristics of the syndrome and overeating issues. These differences reflect the primary pathogenetic role of without the pathogenetic contribution of the other genes included in the typical 17p11.2 deletion. The better comprehension of physiological roles of , its molecular co-workers and interactors, and its contribution in determining the typical SMS phenotype will certainly open a new path for therapeutic interventions.

Background Bleeding anomalies have been reported in patients affected by Noonan syndrome. No study has been performed in patients with molecularly confirmed RASopathy. We aimed to characterize the frequency and types of bleeding disorders in patients with RASopathies and evaluate any significant association with laboratory findings. Patients and methods Forty-nine individuals ( PTPN11 , n = 27; SOS1 , n = 7; RIT1 , n = 3; SPRED1 , n = 1; LZTR1 , N = 3; RAF1 , n = 2; BRAF , n = 4; MEK1 , n = 1; MEK2 , n = 1), and 49 age- and sex-matched controls were enrolled. The “Paediatric Bleeding Questionnaire Scoring Key” was administered to patients and families. Laboratory screening tests including clotting factors dosing, platelet count, Prothrombin Time and Partial Thromboplastin Time, were employed both in patients and controls to characterize the bleeding diathesis. A subgroup of 29/49 patients and 29/49 controls was also tested for platelet function. Results Regardless of the gene involved, pathological paediatric bleeding scores were recorded in 14/49 (28.5%) patients. Indeed, 7 were mutated in PTPN11 , 3 in SOS1 , 2 in RIT1 , 1 in BRAF , and 1 in MEK1 . Compared to patients with normal bleeding scores, those with pathologic bleeding score showed higher prevalence of splenomegaly ( p  = 0.006), prolonged aPTT ( p  = 0.04), lower levels of coagulation factor V (FV, p  = 0.001), FVII ( p  = 0.003), FX ( p  = 0.0008) and FXIII ( p  = 0.002), higher vWAg ( p  = 0.04), and lower platelet sensitivity to Ristocetin ( p  = 0.001), arachidonic acid (AA) ( p  = 0.009) and collagen ( p  = 0.01). The presence of hematomas inversely correlated with factor V ( p  = 0.002), factor VII ( p  = 0.003), factor X ( p  = 0.002) and factor XIII ( p  = 0.004) levels, and directly correlated with platelet response to collagen ( p  = 0.02) and AA ( p  = 0.01). The presence of splenomegaly directly correlated with the presence of hematoma ( p  = 0.006), platelet response to Ristocetin ( p  = 0.04) and AA ( p  = 0.04), and inversely correlated with factor V levels ( p  = 0.03). Conclusions Patients with RASopathies and a bleeding tendency exhibit multiple laboratory abnormalities, including platelet-related disorders. Splenomegaly is frequently detected and might be a suggestive sign for qualitative platelet dysfunction. A comprehensive clinical assessment should be carried out at diagnosis, during the follow-up and before any surgical procedures. Since there is currently no consensus on management of bleeding complications, it is important that physicians closely monitor these patients.

Celiac Disease (CD) occurs in patients with Type 1 Diabetes (T1D) ranging the prevalence of 4.4-11.1% versus 0.5% of the general population. The mechanism of association of these two diseases involves a shared genetic background: HLA genotype DR3-DQ2 and DR4-DQ8 are strongly associated with T1D, DR3-DQ2 with CD. The classical severe presentation of CD rarely occurs in T1D patients, but more often patients have few/mild symptoms of CD or are completely asymptomatic (silent CD). In fact diagnosis of CD is regularly performed by means of the screening in T1D patients. The effects of gluten-free diet (GFD) on the growth and T1D metabolic control in CD/T1D patient are controversial. Regarding of the GFD composition, there is a debate on the higher glycaemic index of gluten-free foods respect to gluten-containing foods; furthermore GFD could be poorer of fibers and richer of fat. The adherence to GFD by children with CD-T1D has been reported generally below 50%, lower respect to the 73% of CD patients, a lower compliance being more frequent among asymptomatic patients. The more severe problems of GFD adherence usually occur during adolescence when in GFD non compliant subjects the lowest quality of life is reported. A psychological and educational support should be provided for these patients.

Noonan syndrome (NS) is an autosomal dominant disease caused by aberrant up-regulated signaling through RAS GTPase. It is characterized by facial dysmorphisms, short stature, congenital heart defects, malformations of rib cage bones, bleeding problems, learning difficulties, or mild intellectual disability. Additional intracranial findings in NS patients include tumors, midline anomalies, and malformations of cortical development. In this report, we present the case of a young female patient, with a known diagnosis of Noonan syndrome that in complete well being developed two brain lesions, in the right nucleus pallidus and in the left cerebellar hemisphere respectively, whose location and signal on MRI looked similar to neurofibromatosis type 1 unidentified bright objects (UBOs), and whose spectroscopic characteristics excluded neoplasms.

BackgroundSchizophrenia (SCZ) is a debilitating mental illness characterized by a highly complex, heterogeneous, non-mendelian genetic background. Recent progress in dissecting genetic architecture of SCZ has accelerated over the last decade due to new advanced technologies. Genome-Wide Association Studies (GWAS) on extremely large samples of patients identified and replicated hundreds of Single-Nucleotide Polymorphism (SNPs), each exhibiting only a modest effect. The analysis of genomic Copy Number Variations (CNVs) clarified the role of rare structural variants conferring significant risk by disrupting multiple genes involved in neurodevelopmental pathways, and linked to SCZ. In this scenario, the aim of our study is to carry out a genetic characterization of a cohort of patients affected by SCZ, in order to assess the risk of recurrence, to elucidate putative pathogenetic mechanisms and, whenever possible, to conceive tailored interventions and therapies.Methods34 patients (8 women and 26 men) affected by SCZ and admitted to Day Hospital at Psychiatric Division for Treatment Resistant Psychosis of the University of Naples Federico II were recruited, and underwent: i) psychopathological evaluation and assessment of clinical response to antipsychotics; ii) genetic counseling; iii) further diagnostic investigation by using Comparative Genomic Hybridization (CGH) + Single Nucleotide Polymorphism (SNP) microarray with 2x400k Agilent’s platform “GenetiSure” for detecting unbalanced chromosomal abnormalities and regions of homozygosity (ROHs).ResultsStructural pathogenetic rearrangements resulted in 9 (27%) patients. Those identified were the following: 15q13.3 deletion, 16p13.11 duplication, 22q11.22 deletion (TOP3B), 22q11.22 (PRODH, DGCR5, DGCR6), RBFOX1 deletion, TCF4 deletion, derivative X chromosome (X;Y translocation).Potentially pathogenic rearrangements, involving genes associated with psychiatric disorders or implicated in neurodevelopment, resulted in 15 patients (44%).No relevant CNVs were detected in 10 patients (29%), although they showed the presence of ROHs that may contain susceptibility loci, since many neurodevelopmental genes map onto or near these specific regions.Certain of these rearrangements occur in many patients, and certain patients showed likewise multiple rearrangements.DiscussionThe analysis of CNVs and SNPs allowed us to characterize the genetic disease structure in the whole cohort of patients and helped to refine the diagnosis in a few cases, thereby ascertaining an underlying specific genetic condition. A further extension of the study, in terms of sample size and more accurate investigations (i.e genetic mapping of ROHs) is underway. According to literature, rare risk-associated CNVs account for 2% of SCZ cases, but their higher prevalence (27%) in our sample may be influenced by a larger percentage of Treatment Resistant and more severely ill patients (since they were recruited in a highly specialized Unit for Treatment Resistant Psychosis). Therefore, our future purpose is to demonstrate a robust genetic modulation of Treatment Resistant endophenotypes of SCZ.Moreover, we believe that the role of genetic counseling in psychiatric services should be emphasized, and that genetic testing in this field should not be restricted to suspected childhood neuropsychiatric disorders. According to the neurodevelopmental hypothesis of SCZ, that suggests a brain development disruption in early life (due to genetic and early environmental factors), prompting to a subsequent later emergence of the disease in adulthood, even chronic complex adult mental illness, such as SCZ, deserves detailed investigations and a more exhaustive genetic evaluation.